Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada.
J Med Chem. 2013 Feb 28;56(4):1520-34. doi: 10.1021/jm301311c. Epub 2013 Feb 7.
The synthesis of a series of new zinc phthalocyanine-peptide conjugates targeting the gastrin-releasing peptide (GRP) and integrin receptors is reported. Two alternative synthetic methods based on Sonogashira cross-coupling of an iodinated zinc phthalocyanine with acetylenic bombesin or arginine-glycine-aspartic acid (RGD) derivatives, either in solution or on solid phase, are presented. The water-soluble conjugates were screened for their photodynamic efficacy against several cancer cell lines expressing different levels of GRP and integrin receptors, and their intracellular localization was evaluated via confocal fluorescence microscopy. Variations in photocytotoxicity between the conjugates correlate to differences in hydrophobicity as well as receptor-mediated cell uptake. In the case of the phthalocyanine-bombesin conjugate, competition experiments confirm the involvement of the GRP receptor in both the phototherapeutic activity as well as intracellular localization. These findings warrant further in vivo studies to evaluate the potential of this conjugate as photosensitizer for photodynamic therapy (PDT) of cancers overexpressing the GRP receptor.
本文报道了一系列新型锌酞菁-肽缀合物的合成，这些缀合物靶向胃泌素释放肽（GRP）和整合素受体。本文提出了两种基于 Sonogashira 交叉偶联反应的替代合成方法，该反应将碘代锌酞菁与乙酰基蛙皮素或精氨酸-甘氨酸-天冬氨酸（RGD）衍生物在溶液或固相中的反应。对具有不同 GRP 和整合素受体表达水平的几种癌细胞系进行了水可溶性缀合物的光动力功效筛选，并通过共聚焦荧光显微镜评估了它们的细胞内定位。缀合物的光细胞毒性变化与疏水性以及受体介导的细胞摄取有关。在锌酞菁-蛙皮素缀合物的情况下，竞争实验证实 GRP 受体参与了光疗活性和细胞内定位。这些发现为进一步的体内研究提供了依据，以评估该缀合物作为过表达 GRP 受体的癌症光动力疗法（PDT）的光敏剂的潜力。
